Candidate Goals and Career Development Plan: The candidate is a cardiothoracic surgeon with the long- term goal of becoming an independent investigator in an academic medical center. The candidate has learned skills in basic immunological research with a special focus on transplantation immunology. This award will provide support needed to develop the foundation of knowledge and skills required for successful long-term investigation. This foundation will be built over the proposed five years of the award by (1) understanding how vascular endothelial cells induce allogeneic regulatory CD4+ T cells, (2) understanding how activation of innate immune responses influences this process, (3) acquiring detailed knowledge about immune regulation and innate immunity and (4) gathering data for the development of an independent project in developing strategies to induce immunological tolerance to solid organ grafts with a particular focus on lung transplantation. Environment: The environment at Washington University in St. Louis is rich in the availability of expertise in immunology in general. The candidate's sponsor is a nationally and internationally recognized independent investigator with expertise in innate immunity and antigen presentation. The applicant's co-sponsor is a world-renowned lung transplant surgeon, who is also well recognized as an independent investigator in ischemia-reperfusion injury of lung allografts. The candidate has a well-equipped laboratory and a full-time research technician whose salary is supported by the Department. Research Proposal: The primary aim of this grant proposal is to investigate the immunological consequences of interactions between vascular endothelium and allogeneic CD4+ T lymphocytes. Preliminary data indicate that CD4+ T lymphocytes acquire strain-specific regulatory function after co-culture with allogeneic vascular endothelial cells. We plan to identify the mechanism underlying this induction of CD4+ T lymphocytes with regulatory properties. Furthermore, we will examine their generation and their regulatory properties in in vivo models that have been well described in our laboratory. Finally, preliminary data suggest that activation of the innate immune system may disrupt the induction of CD4* T cells with regulatory properties by vascular endothelial cells. We plan to study the impact of innate immune system activation on this process.